Candida albicans is an often encountered agent responsible for opportunistic infections in a compromised host. It is one of the most highly prevalent micro-organisms causing secondary disease in patients weakened by cancer, immunosuppressive therapy, radiation treatment, or other debilitating conditions found in hospital-associated infections. Progress in chemotherapy of deep-seated fungal infections in general and candidiasis, in particular, has lagged far behind the spectacular advances in antibacterial antibiotics during the last few decades. We propose to design and synthesize drugs that are selectively toxic for Candida albicans. This is to be accomplished by using the peptide transport system to carry toxic agents into this fungus and, at the same time, prevent the uptake of the peptide-drug conjugates into host tissue because of the structural restrictions for mammalian peptide permeation. The structural and stereochemical requirements of the C. albicans peptide transport system will be examined in detail by measuring the growth response of C. albicans auxotrophs to peptide derivatives containing the required amino acid. Concurrently we will synthesize radioactive peptides that will be used to directly assay peptide transport. The nature and specificity of the array of peptidases present in C. albicans will be thoroughly investigated. Knowledge gained from such investigations will be used to design and then synthesize toxic peptides or peptide-drug conjugates which will be specifically transported by Candida and not by human tissue. Both in vitro systems and animal model infections will be used to determine the efficacy of the anticandidal drugs.